Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease

Jacob Bergstedt; Joëlle A. Pasman; Ziyan Ma; Arvid Harder; Shuyang Yao; Nadine Parker; Jorien L. Treur; Dirk J.A. Smit; Oleksandr Frei; Alexey A. Shadrin; Joeri J. Meijsen; Qing Shen; Sara Hägg; Per Tornvall; Alfonso Buil; Thomas Werge; Jens Hjerling-Leffler; Thomas D. Als; Anders D. Børglum; Cathryn M. Lewis; Andrew M. McIntosh; Unnur A. Valdimarsdóttir; Ole A. Andreassen; Patrick F. Sullivan; Yi Lu; Fang Fang

doi:10.1038/s44161-024-00488-y

Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease

Jacob Bergstedt^*, Joëlle A. Pasman, Ziyan Ma, Arvid Harder, Shuyang Yao, Nadine Parker, Jorien L. Treur, Dirk J.A. Smit, Oleksandr Frei, Alexey A. Shadrin, Joeri J. Meijsen, Qing Shen, Sara Hägg, Per Tornvall, Alfonso Buil, Thomas Werge, Jens Hjerling-Leffler, Thomas D. Als, Anders D. Børglum, Cathryn M. LewisAndrew M. McIntosh, Unnur A. Valdimarsdóttir, Ole A. Andreassen, Patrick F. Sullivan, Yi Lu, Fang Fang

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

1 Citationer (Scopus)

9 Downloads (Pure)

Abstract

Major depressive disorder (MDD) and cardiovascular disease (CVD) are often comorbid, resulting in excess morbidity and mortality. Here we show that CVDs share most of their genetic risk factors with MDD. Multivariate genome-wide association analysis of shared genetic liability between MDD and atherosclerotic CVD revealed seven loci and distinct patterns of tissue and brain cell-type enrichments, suggesting the involvement of the thalamus. Part of the genetic overlap was explained by shared inflammatory, metabolic and psychosocial or lifestyle risk factors. Our data indicated causal effects of genetic liability to MDD on CVD risk, but not from most CVDs to MDD, and showed that the causal effects were partly explained by metabolic and psychosocial or lifestyle factors. The distinct signature of MDD–atherosclerotic CVD comorbidity suggests an immunometabolic subtype of MDD that is more strongly associated with CVD than overall MDD. In summary, we identified biological mechanisms underlying MDD–CVD comorbidity and modifiable risk factors for prevention of CVD in individuals with MDD.

Originalsprog	Engelsk
Tidsskrift	Nature Cardiovascular Research
Vol/bind	3
Udgave nummer	6
Sider (fra-til)	754-769
Antal sider	16
DOI	https://doi.org/10.1038/s44161-024-00488-y
Status	Udgivet - 2024

Bibliografisk note

Funding Information:
This work was supported by European Union\u2019s Horizon 2020 Research and Innovation Programme (CoMorMent project; grant no. 847776). J.A.P. was supported by the US National Institutes of Mental Health (R01MH123724) and the Amsterdam University Medical Center Postdoc Career Bridging grant (27527). N.P. was supported by the Marie Sk\u0142odowska-Curie Actions Grant 801133 (Scientia fellowship) and RCN 300309. J.L.T. is supported by a European Research Council Starting grant (UNRAVEL-CAUSALITY, grant number 101076686) and a Senior Scientist Dekker Grant from the Dutch Heart Foundation (project number 03-004-2022-0055). Q.S. was supported by the Outstanding Clinical Discipline Project of Shanghai Pudong (no. PWYgy2021-02), the Talent training project of the three-year action plan (2023\u20132025) for strengthening the construction of the public health system in Shanghai (no. GWVI-11.2-YQ14), the Interdisciplinary Joint Research Project of Tongji University (2023-3-YB-05) and the Fundamental Research Funds for the Central Universities. C.M.L. is part-funded by the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King\u2019s College London. A.M.M. is supported by the Wellcome Trust (220857/Z/20/Z) and UKRI (MR/W014386/1). A.D.B. was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003) and NIH/NIMH (1R01MH124851-01). O.A.A. was supported by the European Union\u2019s Horizon 2020 research and innovation program (grant agreement nos. 847776 and 964874), Research Council of Norway (223273, 296030, 326813 and 324499). P.F.S. gratefully acknowledges support from the Swedish Research Council (Vetenskapsr\u00E5det, award D0886501), the US National Institutes of Mental Health (R01s MH124871, MH121545 and MH123724) and the Horizon 2020 Programme of the European Union (grant agreement no. 847776). Y.L. was supported by the European Research Council (grant agreement ID 101042183). We acknowledge HERMES and CARDIoGRAMplusC4D consortia for contributing data and guidance. The PRS analyses have been conducted using the UKB resource under application number 22224. They were enabled by resources in project sens2017519 provided by the National Academic Infrastructure for Supercomputing in Sweden at UPPMAX, funded by the Swedish Research Council through grant agreement no. 2022-06725. This work was performed on Services for Sensitive Data, University of Oslo, with resources provided by UNINETT Sigma2, the national infrastructure for high performance computing and data storage in Norway.

Publisher Copyright:
© The Author(s) 2024.

Adgang til dokumentet

10.1038/s44161-024-00488-yLicens: CC BY

FulltextForlagets udgivne version, 6,09 MBLicens: CC BY

Citationsformater

Bergstedt, J., Pasman, J. A., Ma, Z., Harder, A., Yao, S., Parker, N., Treur, J. L., Smit, D. J. A., Frei, O., Shadrin, A. A., Meijsen, J. J., Shen, Q., Hägg, S., Tornvall, P., Buil, A., Werge, T., Hjerling-Leffler, J., Als, T. D., Børglum, A. D., ... Fang, F. (2024). Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease. Nature Cardiovascular Research, 3(6), 754-769. https://doi.org/10.1038/s44161-024-00488-y

Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease. / Bergstedt, Jacob; Pasman, Joëlle A.; Ma, Ziyan; Harder, Arvid; Yao, Shuyang; Parker, Nadine; Treur, Jorien L.; Smit, Dirk J.A.; Frei, Oleksandr; Shadrin, Alexey A.; Meijsen, Joeri J.; Shen, Qing; Hägg, Sara; Tornvall, Per; Buil, Alfonso; Werge, Thomas; Hjerling-Leffler, Jens; Als, Thomas D.; Børglum, Anders D.; Lewis, Cathryn M.; McIntosh, Andrew M.; Valdimarsdóttir, Unnur A.; Andreassen, Ole A.; Sullivan, Patrick F.; Lu, Yi; Fang, Fang.

I: Nature Cardiovascular Research, Bind 3, Nr. 6, 2024, s. 754-769.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Bergstedt, J, Pasman, JA, Ma, Z, Harder, A, Yao, S, Parker, N, Treur, JL, Smit, DJA, Frei, O, Shadrin, AA, Meijsen, JJ, Shen, Q, Hägg, S, Tornvall, P, Buil, A, Werge, T, Hjerling-Leffler, J, Als, TD, Børglum, AD, Lewis, CM, McIntosh, AM, Valdimarsdóttir, UA, Andreassen, OA, Sullivan, PF, Lu, Y & Fang, F 2024, 'Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease', Nature Cardiovascular Research, bind 3, nr. 6, s. 754-769. https://doi.org/10.1038/s44161-024-00488-y

Bergstedt, Jacob ; Pasman, Joëlle A. ; Ma, Ziyan ; Harder, Arvid ; Yao, Shuyang ; Parker, Nadine ; Treur, Jorien L. ; Smit, Dirk J.A. ; Frei, Oleksandr ; Shadrin, Alexey A. ; Meijsen, Joeri J. ; Shen, Qing ; Hägg, Sara ; Tornvall, Per ; Buil, Alfonso ; Werge, Thomas ; Hjerling-Leffler, Jens ; Als, Thomas D. ; Børglum, Anders D. ; Lewis, Cathryn M. ; McIntosh, Andrew M. ; Valdimarsdóttir, Unnur A. ; Andreassen, Ole A. ; Sullivan, Patrick F. ; Lu, Yi ; Fang, Fang. / Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease. I: Nature Cardiovascular Research. 2024 ; Bind 3, Nr. 6. s. 754-769.

@article{679524ff875c4da9b3fd6300e2584e8e,

title = "Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease",

abstract = "Major depressive disorder (MDD) and cardiovascular disease (CVD) are often comorbid, resulting in excess morbidity and mortality. Here we show that CVDs share most of their genetic risk factors with MDD. Multivariate genome-wide association analysis of shared genetic liability between MDD and atherosclerotic CVD revealed seven loci and distinct patterns of tissue and brain cell-type enrichments, suggesting the involvement of the thalamus. Part of the genetic overlap was explained by shared inflammatory, metabolic and psychosocial or lifestyle risk factors. Our data indicated causal effects of genetic liability to MDD on CVD risk, but not from most CVDs to MDD, and showed that the causal effects were partly explained by metabolic and psychosocial or lifestyle factors. The distinct signature of MDD–atherosclerotic CVD comorbidity suggests an immunometabolic subtype of MDD that is more strongly associated with CVD than overall MDD. In summary, we identified biological mechanisms underlying MDD–CVD comorbidity and modifiable risk factors for prevention of CVD in individuals with MDD.",

author = "Jacob Bergstedt and Pasman, {Jo{\"e}lle A.} and Ziyan Ma and Arvid Harder and Shuyang Yao and Nadine Parker and Treur, {Jorien L.} and Smit, {Dirk J.A.} and Oleksandr Frei and Shadrin, {Alexey A.} and Meijsen, {Joeri J.} and Qing Shen and Sara H{\"a}gg and Per Tornvall and Alfonso Buil and Thomas Werge and Jens Hjerling-Leffler and Als, {Thomas D.} and B{\o}rglum, {Anders D.} and Lewis, {Cathryn M.} and McIntosh, {Andrew M.} and Valdimarsd{\'o}ttir, {Unnur A.} and Andreassen, {Ole A.} and Sullivan, {Patrick F.} and Yi Lu and Fang Fang",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

doi = "10.1038/s44161-024-00488-y",

language = "English",

volume = "3",

pages = "754--769",

journal = "Nature Cardiovascular Research",

issn = "2731-0590",

publisher = "Springer Nature [academic journals on nature.com]",

number = "6",

}

TY - JOUR

T1 - Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease

AU - Bergstedt, Jacob

AU - Pasman, Joëlle A.

AU - Ma, Ziyan

AU - Harder, Arvid

AU - Yao, Shuyang

AU - Parker, Nadine

AU - Treur, Jorien L.

AU - Smit, Dirk J.A.

AU - Frei, Oleksandr

AU - Shadrin, Alexey A.

AU - Meijsen, Joeri J.

AU - Shen, Qing

AU - Hägg, Sara

AU - Tornvall, Per

AU - Buil, Alfonso

AU - Werge, Thomas

AU - Hjerling-Leffler, Jens

AU - Als, Thomas D.

AU - Børglum, Anders D.

AU - Lewis, Cathryn M.

AU - McIntosh, Andrew M.

AU - Valdimarsdóttir, Unnur A.

AU - Andreassen, Ole A.

AU - Sullivan, Patrick F.

AU - Lu, Yi

AU - Fang, Fang

PY - 2024

Y1 - 2024

N2 - Major depressive disorder (MDD) and cardiovascular disease (CVD) are often comorbid, resulting in excess morbidity and mortality. Here we show that CVDs share most of their genetic risk factors with MDD. Multivariate genome-wide association analysis of shared genetic liability between MDD and atherosclerotic CVD revealed seven loci and distinct patterns of tissue and brain cell-type enrichments, suggesting the involvement of the thalamus. Part of the genetic overlap was explained by shared inflammatory, metabolic and psychosocial or lifestyle risk factors. Our data indicated causal effects of genetic liability to MDD on CVD risk, but not from most CVDs to MDD, and showed that the causal effects were partly explained by metabolic and psychosocial or lifestyle factors. The distinct signature of MDD–atherosclerotic CVD comorbidity suggests an immunometabolic subtype of MDD that is more strongly associated with CVD than overall MDD. In summary, we identified biological mechanisms underlying MDD–CVD comorbidity and modifiable risk factors for prevention of CVD in individuals with MDD.

AB - Major depressive disorder (MDD) and cardiovascular disease (CVD) are often comorbid, resulting in excess morbidity and mortality. Here we show that CVDs share most of their genetic risk factors with MDD. Multivariate genome-wide association analysis of shared genetic liability between MDD and atherosclerotic CVD revealed seven loci and distinct patterns of tissue and brain cell-type enrichments, suggesting the involvement of the thalamus. Part of the genetic overlap was explained by shared inflammatory, metabolic and psychosocial or lifestyle risk factors. Our data indicated causal effects of genetic liability to MDD on CVD risk, but not from most CVDs to MDD, and showed that the causal effects were partly explained by metabolic and psychosocial or lifestyle factors. The distinct signature of MDD–atherosclerotic CVD comorbidity suggests an immunometabolic subtype of MDD that is more strongly associated with CVD than overall MDD. In summary, we identified biological mechanisms underlying MDD–CVD comorbidity and modifiable risk factors for prevention of CVD in individuals with MDD.

U2 - 10.1038/s44161-024-00488-y

DO - 10.1038/s44161-024-00488-y

M3 - Journal article

C2 - 38898929

AN - SCOPUS:85196089284

VL - 3

SP - 754

EP - 769

JO - Nature Cardiovascular Research

JF - Nature Cardiovascular Research

SN - 2731-0590

IS - 6

ER -